Levosimendan is a highly potent cardiotonic that increases the sensitivity of the heart to calcium without causing a rise in intracellular calcium. The drug is marketed by Abbott under the trade name Simdax. It was first disclosed in U.S. Pat. No. 5,569,657.
The prior art indicates that pure levosimendan can be obtained by passing the racemic mixture over a chiral phase chromatography column. But the process becomes tedious and industrially unacceptable when a large quantity of material is involved.
One prior art technique involves using the optically-pure (−)-enantiomer of 6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one as starting material. The method of obtaining (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one is given in EP208518, which describes the separation of pure enantiomers of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone using a chiral HPLC column.
CN1616437 describes treating (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone with 50% alkali or 50% acid.
JP10109977 discloses the use of 1-propanol/ethyl acetate as resolving solvent and L- or D-tartaric acid as resolving agent.
U.S. Pat. No. 5,569,657 discloses the preparation of levosimendan and its salts. (±)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one is dissolved in 2-propanol on heating. L-tartaric acid is gradually added to the solution and stirred on heating to obtain a clear solution. The solution is cooled slowly to room temperature and then stirred overnight at 200 C to obtain a crystalline product. On filtering, the wet salt is dissolved in water and to it potassium carbonate solution is added with stirring. The free base obtained is filtered, washed with water and dried. The product is further dissolved in dioxane on heating and allowed to cool to room temperature. The contents are filtered and dried under vacuum to obtain (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one crystalline solid. The pure (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one compound is then treated with sodium nitrite and malononitrile under acidic condition to obtain levosimendan. A disadvantage of the resolution process disclosed is that to obtain a high optical purity (99.5%) of the pyridazinone compound, recrystallisation with dioxane is required. Also the process involves multiple steps and is time consuming.
U.S. Pat. No. 6,180,789 describes the preparation of levosimendan by treating the (−)-enantiomer of 6-(4-amino phenyl)-5-methylpyridazin-3-(2H)-one, resolved using D- or L-tartaric acid in aqueous ethyl acetate, with sodium nitrite and malononitrile and further crystallizing with aqueous acetone. The patent also discloses other resolving agents such as benzoic acid, sulphuric acid, and resolving solvents such as isopropanol, isobutanol, isopropyl acetate, butyl acetate, acetone and acetonitrile. These conditions are said to cause partial resolution only.
There are certain drawbacks of the process disclosed in U.S. Pat. No. 6,180,789—
When D-tartaric acid is the resolving agent—
                Excess amount of resolving agent is required to achieve complete resolution.        Seeding with D-tartaric acid salt of (−)-6-(4-amino phenyl)-5-methylpyridazin-3-(2H)-one is also needed in the process.        Hot filtration of the precipitate is to be done; which is not at all workable when dealing with large batches at industrial scale.        The temperature of reaction is to be maintained at 0° C.        The enantiomeric purity of the product is low, even after giving a number of washings.        In order to obtain the desired enantiomeric excess, it is necessary to perform recrystallisation with acetonitrile in the presence of absorbent followed by washing with excess acetonitrile. Treatment with a large amount of solvent increases the cost of process and also reduces the yield due to wastage.        
When L-tartaric acid is the resolving agent—                For the precipitation of salt, cooling up to −10° C. is required.        The enantiomeric purity of the desired (−)-6-(4-amino phenyl)-5-methylpyridazin-3-(2H)-one product is quite low (78.7%).        
Due to the problems with the prior art there is felt a need to develop a new process for resolving levosimendan that is simple, economical, eco-friendly and high-yielding.